HEPATIC AND EXTRAHEPATIC SYNTHESIS AND DISPOSITION OF DINITROPHENYL-SGLUTATHIONE IN BILE DUCT-LIGATED RATS

VILLANUEVA SSM; RUIZ ML; SOROKA CJ; CAI SY; LUQUITA MG; TORRES AM; SÁNCHEZ POZZI EJ; PELLEGRINO JM; BOYER JL; CATANIA VA; MOTTINO AD

Drug Metabolism and Disposition

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS

Año: 2006 vol. 34 p. 1301 - 1309

0090-9556

The ability of the kidney and small intestine to synthesize andsubsequently eliminate dinitrophenyl-S-glutathione (DNP-SG), asubstrate for the multidrug resistance-associated proteins (Mrps),was assessed in bile duct-ligated (BDL) rats 1, 7, and 14 days aftersurgery, using an in vivo perfused jejunum model with simultaneousurine collection. A single i.v. dose of 30 mol/kg b.wt. of1-chloro-2,4-dinitrobenzene (CDNB) was administered, and its glutathioneconjugate DNP-SG and dinitrophenyl cysteinyl glycinederivative, which is the result of -glutamyl-transferase action onDNP-SG, were determined in urine and intestinal perfusate byhigh-performance liquid chromatography. Intestinal excretion ofthese metabolites was unchanged at day 1, and decreased at days7 and 14 (39% and 33%, respectively) after surgery with respectto shams. In contrast, renal excretion was increased by 114%,150%, and 128% at days 1, 7, and 14. Western blot studies revealeddecreased levels of apical Mrp2 in liver and jejunum but increasedlevels in renal cortex from BDL animals, these changes beingmaximal between days 7 and 14. Assessment of expression ofbasolateral Mrp3 at day 14 postsurgery indicated preserved levelsin renal cortex, duodenum, jejunum, distal ileum, and colon. Analysisof expression of glutathione-S-transferases , , and , aswell as activity toward CDNB, indicates that formation of DNP-SGwas impaired in liver, preserved in intestine, and increased in renalcortex. In conclusion, increased renal tubular conversion of CDNBto DNP-SG followed by subsequent Mrp2-mediated secretion intourine partially compensates for altered liver function in experimentalobstructive cholestasis.